Broad range anti-cancer chemotherapeutic agents frequently act by inhibiting proliferation by disrupting cell division or inhibiting apoptosis in relatively rapidly dividing cells. One strategy is to inhibit cell proliferation is to use nucleotide analog chemotherapeutic agents such as cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, capecitabine, cytarabine, decitabine, fluorouracil, floxuridine, sapacitabine, and gemcitabine. The compounds are structurally similar and typically act by at least interfering with DNA replication. Nucleotide analog chemotherapeutic agents are used to treat, or are under study for treatment of, a variety of cancers including hematological malignancies such as leukemia and lymphoma, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, basal cell carcinoma, bladder cancer, hepatic cancer, prostate cancer, gastric cancer, renal cancer, melanoma, glioma, esophageal cancer, cervical cancer, and myelodysplastic syndromes.
Treatment with chemotherapeutic agents frequently results in the development of resistance to one or more chemotherapeutic drugs by various mechanisms. For example, gemcitabine resistance in cancer is a widespread problem. A large proportion of cancer patients end up receiving gemcitabine at some point of their care as is approved in lung, pancreatic, bladder, breast, and ovarian cancer, and is being investigated for the treatment of at least hepatic and esophageal cancer and is used for the treatment of lymphomas and other cancers experimentally. Although efficacious in a third of the cases for which the drug is approved, most do not respond, and even those who respond eventually develop resistance.
Gemcitabine resistance is particularly problematic in pancreatic cancer for which there are not other proven chemotherapeutic regimens. Despite advances in treatment of many types of cancer, pancreatic cancer remains difficult to treat with low long term survival. In 2004 the estimated incidence of the disease in the USA is 31,860 with an expected 31,270 deaths. One of the limitations of new drug development is the lack of appropriate preclinical models.
Overall, about 5% of patients with cancer of the exocrine pancreas will be alive 5 years after the cancer is found. Even for those with local disease, the 5-year relative survival rate is about 20%. For those who have regional disease, the 5-year relative survival rate is about 8%. If there are metastases, the 5-year relative survival rate is 2%. Although gemcitabine is approved for treatment for pancreatic cancer patients, about 75% to 90% of patients have minimal benefit from this therapy. No evidence-based treatment recommendation can be given for patients with advanced pancreatic cancer after failure of first line gemcitabine treatment.
Over the last few years, a significant number of clinical trials have explored the activity of new agents in pancreatic cancer alone or in combination with gemcitabine. The results of these studies have been mostly negative. Despite activity data in phase II studies, no single agent or combination strategy has been superior to gemcitabine alone in studies conducted thus far. This applies not only to conventional drugs but also to targeted agents such as matrix metalloproteinase (MMP) and farnesyl-transferase inhibitors (FTI).
Studies have been performed to identify appropriate treatments for pancreatic cancer patients who have failed gemcitabine therapy, but the results have been mixed. In one study, treatment consisted of docetaxel 65 mg/m2 and irinotecan 160 mg/m2, both administered every 21 days. Fourteen patients were enrolled before the study was closed due to excess toxicity. The most common grade 3/4 toxicities included neutropenia/leukopenia, nausea and vomiting, and diarrhea. Fully half of patients received only 1 treatment cycle, with a median time to treatment failure of 36 days. No objective responses were observed, although 3 patients had stable disease for at least 6 cycles. Overall survival for the entire cohort was 134 days, with a 6-month survival rate of 36%. In another study, patients with gemcitabine-resistant pancreatic cancer were treated with S-1 plus cisplatin (CDDP) to determine response rate and toxicity. Five of seventeen patients enrolled (29.4%) achieved a partial response and 2 (11.8%) had stable disease. Toxicities of the treatment were acceptable. The median survival time was 10 months (range, 20 months), with 63.7% and 31.9% of patients alive at 6 and 12 months, respectively.